Pulmonary hypertension is characterized by profound changes in the structure of the arterial wall due in large part, to the proliferation of smooth muscle cells. Insults to the cardiopulmonary system elicit changes in SMC phenotype through a variety of mechanisms including the production of proliferative and inflammatory cytokines by endothelial cells and platelets. The long-term goals of our research are to define the molecular mechanisms by which the cytokine, Platelet-derived Growth Factor-BB (PDGF-BB) regulates pulmonary artery (PA) SMC proliferation. Previously, we reported that levels of the transcription factor, cAMP-Response Element Binding Protein (CREB) are reduced in proliferating SMCs in PAs from hypertensive, neonatal cows, or in cultured SMCs treated with PDGF-BB. We also demonstrated that ectopic expression of constitutively active CREB isoforms in SMCs inhibits basal and PDGF-induced growth in vitro, whereas dominant negative CREB isoforms enhanced proliferation. PDGF appears to regulate CREB content at the level of gene transcription. Interestingly, PPARg agonists increased CREB content and blocked SMC proliferation in vitro and in rodent models of diabetic vascular disease. Recent preliminary studies indicate that CREB modulates cyclin D1 and Cdk-4 expression in SMCs. Based on these results, we hypothesize that PDGF-BB regulates SMC proliferation via associated signaling pathways and transcription factors that control CREB gene transcription, which in turn controls the expression of factors that govern cell cycle entry and progression like cyclin D1 and Cdk-4. To address this hypothesis we have designed three Specific Aims to 1) identify the intracellular signaling pathways and transcription factors that regulate CREB gene transcription in response to PDGF-BB, 2) demonstrate that CREB-induced changes in cyclin D1 and Cdk4 regulates SMC proliferation, and 3) demonstrate that PPAR agonists increase CREB content and prevent vascular remodeling in neonatal cows exposed to hypoxic conditions. These studies are significant since CREB has not been widely implicated in SMC function, in spite of the well-established role of cyclic nucleotides and PKA in controlling SMC proliferation. Likewise, the regulation of CREB activity has traditionally been viewed as a function of phosphorylation status rather than changes in CREB content. Defining the expression and regulation of CREB in SMCs is crucial to developing a comprehensive model for its participation in controlling SMC proliferation. The proposed studies should provide new insights into the gene transcription events that control SMC growth and perhaps identify targets for new therapies designed to prevent or treat PH and related diseases.